This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background: Our cerebrospinal fluid proteomics studies identified a specific set of proteins (GWI/CFS proteome) in two separate cohorts of subjects with co-existing Gulf War Illness (GWI) and chronic fatigue syndrome (CFS) compared to healthy control subjects. One critical protein, carnosine dipeptidase 1 (CNDP1), was detected significantly more frequently in GWI (n=4/9) than in healthy controls (n=1/12) Aim 1.b.ii: Advanced statistical modeling of the plasma proteins to identify unique biomarkers of GWI. Hypothesis 1.c: A statistical model of CNDP1 genotype, GWI-related plasma proteins, pain, systemic hyperalgesia, autonomic and muscle function, sleep, quality of life, fatigue and other complaints will predict GWI or subsets of GWI subjects. Aim 1.c: Determine if the LB6B and LB7B alleles predict the plasma proteome, pain, autonomic and muscle dysfunction (isometric hand grip), activity (Actiwatch), quality of life (SF-36), sleep, fatigue, and other common symptoms in GWI. Plan 2: Recruit 100 GWI to a double-blind, placebo-controlled randomized study of oral carnosine. Hypothesis 2: Carnosine improves pain, sleep, and activity after 6 months. Aim 2: Determine if oral carnosine significantly improves activity (Actiwatch), scores for fatigue, pain, sleep, and SF-36 quality of life domains compared to placebo. Plan 3: Genotype neuroblastoma cells for CNDP1. Assess antioxidant effects in cell culture. Hypothesis 3: Carnosine and homocarnosine will protect neuroblastoma cells from oxidant injury and glutamate-induced neurotoxicity. Aim 3: Determine the lethal dose for 50% killing of neuroblastoma cells for HB2BOB2B and glutamate. Determine the dose response effects of carnosine and homocarnosine on these toxic agents. Plan 4: Culture neuroblastoma cells with BMAA, HCO3-, homocarnosine, and carnosine. Hypothesis 4: BMAA from Cyanobacterium in brackish water and dust was toxic in military personnel who have longer CNDP1 genotypes (LB6B, LB7B) and reduced antioxidant dipeptides. BMAA interacts with bicarbonate to form a glutaminergic toxin. Aim 4: Study the biological interactions of these antioxidants on BMAA and bicarbonate toxicity. Impact: The cross-sectional study will identify genetic (CNDP1 alleles) and proteomic biomarkers in GWI. The antioxidant and neuromodulatory effects of homocarnosine, carnosine, and their amino acids provide the rationale for our double-blind, placebo-controlled study of oral carnosine as a treatment for GWI. Both safety and efficacy issues will be addressed prospectively. Neuroblastoma cells will be a model for understanding the functions of these dipeptides and CNDP1, their role in protecting against oxidant and glutamine-mediated neurotoxicity, and the potential neurotoxic effects of cyanobacterial BMAA in GWI and ALS-PD pathogenesis.,